Influenza A viruses (IAVs) cause seasonal outbreaks and occasional severe pandemics that are a significant burden in morbidity, mortality, and economic loss. The continuous evolution of IAV through mutation and reassortment provide molecular mechanisms to allow IAV to evade host immunity. However, there remain significant gaps in our understanding of the tug of war between host and virus, particularly, the molecular mechanisms influenza virus employs through evolution in response to host defense mechanisms and the implications this may have for vaccination strategies. By focusing on the biology, evolution and pathogenesis of the virus, first, we aim to determine the significance and extent of IAV evolution caused by acute primary and memory (vaccination) adaptive immune responses. Specifically, we will utilize next generation sequencing of the full virus genome to determine the kinetics and extent of virus evolution. We will determine whether our current vaccination strategies result in enhanced virus evolution and further whether viral evolution rate could be used as an early indicator of vaccine efficacy. Second, we want to focus on the role of influenza virus protein evolution in viral pathogenesis and transmission. Through these studies, we aim to further our understanding of IAV evolution and the underlying causative host mechanisms. It is hoped that with a better understanding of the highly adaptive IAV, these studies will uncover novel and improved ways to vaccinate and combat IAV infection.